Introduction: Ovarian epithelial carcinomas have a poor prognosis and it is related to the absence of symptoms in the majority of early stages of the disease. Apoptosis is type of cell death that is highly regulated and critically important for maintaining homeostatic cell numbers. Expression of oncogenes, such as bcl-2 , and inactivation of tumour suppressor genes, such as p53, reduce the susceptibility of cells to undergo apoptosis, meanwhile the expression of bax increase it. The check-points proteins has been recognised as a key element in controlling cell division, and cancer. Objective: The tumours of ovary are a heterogeneous type of tumours in which we have studied the apoptosis and checkpoints mechanism in order to establish the importance of this factors in ovarian carcinogenesis, progression and therapeutics response of these tumours. Methods: Tumour specimens from 130 consecutive epithelial tumours of the ovary were examined for over expression of p53, bcl-2, bax, hus-1 and rad-9 proteins. The apoptotic index (AI) was evaluated by modified terminal deoxynucleotydil- transferasa- mediated deoxyuridine triphosphate-biotin nick end-labelling (TUNEL) methods and in Hematoxilin-Eosin stain in histological sections. Other variables such as age, tumour type, FIGO stage, histological grade, necrosis, mitotic index and presence of recurrences and or metastases were also analysed. Statistical analyses were implemented sing the SPSS 10. 0 package. Results : The AI detected by H-E and by TUNEL was high in the majority of carcinomas (serous, endometrioid and clear cell), where as cistoadenomas, tumours of low malignant potential and mucinous carcinomas mostly showed low AI (p=0,001). All benign lesions were p53 negative. The distribution of p53 positive cases was particularly important in serous carcinomas. Strong bcl-2 was seen in benign, and borderline serous tumours. The bcl-2 expression was most often seen in clear cell and endometrioid carcinomas, but infrequent or absent in mucinous borderline tumours, mucinous carcinomas, and serous carcinomas (p=0,034). Increased levels of Bax were related to borderline tumours and to malignant transformation. Similar results were observed with the expression of Hus-1 (p<0,05. In univariate analysis, high AI by H-E and by TUNEL, significantly correlated with shorter survival and shorter free period of illness (p<0,01). In addition, the high expression of p53 was also correlated with adverse prognosis. However the high expression of bcl-2 was correlated with better prognosis (p=0,01). In multivariate analysis the age (p=0,02), the FIGO stage (p=0,017) and the AI (p=0,019) revealed an independent prognostic factors for survival. On the other hand, the age (p=0,01), the FIGO stage (p=0,038), necrosis (p=0,023) and p53 expression (p=0,005) revealed an independent prognostic factors for free period of disease. The Spearman coefficient was 0,75 (p<0,05) between the AI in H-E sections and TUNEL techniques. There were positive correlation between the AI, p53 and bax and the expression of checkpoint protein hus-1 (p<0,05). Conclusions: 1- The high expression in bcl-2 was seen in benign and borderline tumours. Meanwhile the expression of p53 was higher in malignant tumours. 2- There was statistical significant differences in the expression of p53, bcl-2 and bax protein and the AI among the different histological types. 3-There were a positive correlation between the expression of p53 protein and the AI with other prognostic factors. 4 - In univariate analysis the AI, the high expression of p53 and the low expression of bcl-2 significantly correlated with shorter survival. 5- In multivariate survival analysis the AI revealed an independent prognostic factor. 6- In multivariate free period of illness analysis the expression of p53 revealed an independent prognostic factor. 7- The most adequate method evaluate the AI is the hematoxilin-eosin sections. 8- The expression of hus-1 is higher in carcinomas and low in benign and borderline tumours. 9- The expression of hus-1 shows a positive correlation with the AI and with the pro-apoptotic factors.
| Date of Award | 5 Mar 2002 |
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| Original language | Spanish |
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| Supervisor | Jordi Xercavins Montosa (Director) & Ángel García Jiménez (Director) |
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